SPDL1

Summary

SPDL1 (spindle apparatus coiled-coil protein 1, HGNC:26010) is a protein-coding gene on chromosome 5q35.1, encoding Protein Spindly (Q96EA4). Required for the localization of dynein and dynactin to the mitotic kinetochore. It is a common-essential gene (DepMap: required in 99.2% of cancer cell lines).

This gene encodes a coiled-coil domain-containing protein that functions in mitotic spindle formation and chromosome segregation. The encoded protein plays a role in coordinating microtubule attachment by promoting recruitment of dynein proteins, and in mitotic checkpoint signaling.

Source: NCBI Gene 54908 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 108 total — 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 99.2% of screened cell lines (common-essential)
• MANE Select transcript: NM_017785

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26010
Approved symbol	SPDL1
Name	spindle apparatus coiled-coil protein 1
Location	5q35.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20364, hSpindly
Ensembl gene	ENSG00000040275
Ensembl biotype	protein_coding
OMIM	616401
Entrez	54908

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 15 protein_coding, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265295, ENST00000503209, ENST00000503871, ENST00000505977, ENST00000506574, ENST00000507232, ENST00000508247, ENST00000508837, ENST00000509785, ENST00000510751, ENST00000512028, ENST00000513795, ENST00000513941, ENST00000515224, ENST00000523518, ENST00000629457, ENST00000925120, ENST00000925121, ENST00000925122, ENST00000925123, ENST00000925124, ENST00000925125, ENST00000961466

RefSeq mRNA: 6 — MANE Select: NM_017785 NM_001329639, NM_001329640, NM_001329641, NM_001329642, NM_001329643, NM_017785

CCDS: CCDS4370

Canonical transcript exons

ENST00000265295 — 12 exons

Exon	Start	End
ENSE00001928589	169604060	169604778
ENSE00002050435	169583773	169583889
ENSE00002224041	169601280	169601625
ENSE00003506700	169588394	169588575
ENSE00003519894	169591048	169591224
ENSE00003522258	169598476	169598579
ENSE00003526756	169596561	169596701
ENSE00003566079	169598972	169599159
ENSE00003609496	169594145	169594294
ENSE00003623324	169594394	169594492
ENSE00003644931	169593354	169593548
ENSE00003664841	169594571	169594681

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.6450 / max 2614.8559, expressed in 1772 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60088	30.2082	1771
60089	0.4266	183
60090	0.0102	6

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.86	gold quality
oocyte	CL:0000023	97.38	gold quality
ventricular zone	UBERON:0003053	92.79	gold quality
stromal cell of endometrium	CL:0002255	92.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.60	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.96	gold quality
embryo	UBERON:0000922	88.03	gold quality
ganglionic eminence	UBERON:0004023	87.92	gold quality
right testis	UBERON:0004534	86.61	gold quality
left testis	UBERON:0004533	86.29	gold quality
testis	UBERON:0000473	86.17	gold quality
calcaneal tendon	UBERON:0003701	85.58	gold quality
spinal cord	UBERON:0002240	85.54	gold quality
sural nerve	UBERON:0015488	83.80	gold quality
cortical plate	UBERON:0005343	83.75	gold quality
rectum	UBERON:0001052	82.90	gold quality
vermiform appendix	UBERON:0001154	82.76	gold quality
cerebellar hemisphere	UBERON:0002245	82.25	gold quality
cerebellar cortex	UBERON:0002129	82.04	gold quality
adrenal tissue	UBERON:0018303	81.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.49	gold quality
islet of Langerhans	UBERON:0000006	81.31	gold quality
lymph node	UBERON:0000029	80.94	gold quality
esophagus mucosa	UBERON:0002469	80.51	gold quality
cerebellum	UBERON:0002037	80.24	gold quality
smooth muscle tissue	UBERON:0001135	79.94	gold quality
sperm	CL:0000019	79.71	gold quality
gall bladder	UBERON:0002110	78.94	gold quality
colonic epithelium	UBERON:0000397	78.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

40 targeting SPDL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-1288-5P	98.85	67.01	734

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• [hSpindly] Localization of human Spindly (hSpindly) to kinetochores is controlled by the Rod/Zw10/Zwilch (RZZ) complex and Aurora B. (PMID:19468067)
• Spindly is not only required for kinetochore localization of dynein but is a functional component of a mechanism that couples dynein-dependent poleward movement of chromosomes to their efficient attachment to microtubules. (PMID:20427577)
• dynein-mediated removal of Spindly from microtubule-attached kinetochores, rather than poleward transport per se, is the critical reaction in checkpoint silencing (PMID:20439434)
• Farnesylation of Spindly is essential for its localization, & thus for proper localization of dynein & dynactin, to prometaphase kinetochores. Both Spindly and CENP-E farnesylation are required for efficient chromosome congression (PMID:25808490)
• hSpindly is farnesylated in vivo and farnesylation is essential for its interaction with the RZZ complex and hence Kinetochore localization. (PMID:25825516)
• Using mass spectrometry this study identified CCDC99 as a new target of USP45. The data showed that CCDC99 and USP45 are part of the same complex and that their interaction specifically depends on the catalytic activity of USP45. (PMID:30258100)
• SPDL1 knockdown in human CRC cells significantly increased invasion and migration of tumor cells. Lower SPDL1 expression levels are significantly associated with reduced survival in CRC patients. SPDL1 depletion in human CRC cells significantly increases tumor development in xenograft assays. SPDL1 is a human CRC tumor-suppressor genes that acts downstream of MRTFB to regulate CRC growth and survival. (PMID:31690663)
• [Expression and clinical significance of Spindly and Bub3 in oral squamous cell carcinoma]. (PMID:33543222)
• Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis. (PMID:33758299)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	spdl1	ENSDARG00000103996
mus_musculus	Spdl1	ENSMUSG00000069910
rattus_norvegicus	Spdl1	ENSRNOG00000007292

Paralogs (2): BICDL1 (ENSG00000135127), BICDL2 (ENSG00000162069)

Protein

Protein identifiers

Protein Spindly — Q96EA4 (reviewed: Q96EA4)

Alternative names: Arsenite-related gene 1 protein, Coiled-coil domain-containing protein 99, Rhabdomyosarcoma antigen MU-RMS-40.4A, Spindle apparatus coiled-coil domain-containing protein 1

All UniProt accessions (10): D6R936, D6RC83, Q96EA4, D6RCL1, D6RDK5, D6REZ1, D6RIB8, D6RIF7, H0YBG5, H7C5V2

UniProt curated annotations — full annotation on UniProt →

Function. Required for the localization of dynein and dynactin to the mitotic kinetochore. Dynein is believed to control the initial lateral interaction between the kinetochore and spindle microtubules and to facilitate the subsequent formation of end-on kinetochore-microtubule attachments mediated by the NDC80 complex. Also required for correct spindle orientation. Does not appear to be required for the removal of spindle assembly checkpoint (SAC) proteins from the kinetochore upon bipolar spindle attachment. Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Plays a role in cell migration.

Subunit / interactions. Interacts with KNTC1 and ZW10. These interactions appear weak and may be transient or indirect. Interacts with dynein intermediate chain and dynactin (DCTN1). Interacts with the catalytically active form of USP45.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Chromosome. Centromere. Kinetochore. Nucleus. Spindle pole.

Post-translational modifications. Monoubiquitinated with’Lys-48’ linkage. Deubiquitinated by USP45.

Similarity. Belongs to the Spindly family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96EA4-1	1	yes
Q96EA4-2	2
Q96EA4-3	3

RefSeq proteins (6): NP_001316568, NP_001316569, NP_001316570, NP_001316571, NP_001316572, NP_060255* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028593	SPDLY_chordates	Family
IPR051149	Spindly/BICDR_Dynein_Adapter	Family

UniProt features (16 total): modified residue 4, sequence conflict 3, sequence variant 2, splice variant 2, chain 1, region of interest 1, helix 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8ARF	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EA4-F1	75.20	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 1, 513, 515, 555

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-141424	Amplification of signal from the kinetochores
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69618	Mitotic Spindle Checkpoint
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 253 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_SPINDLE_LOCALIZATION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_CHROMOSOME_SEPARATION, KONG_E2F3_TARGETS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOLDRATH_ANTIGEN_RESPONSE

GO Biological Process (6): establishment of mitotic spindle orientation (GO:0000132), mitotic metaphase chromosome alignment (GO:0007080), mitotic spindle assembly checkpoint signaling (GO:0007094), cell migration (GO:0016477), protein localization to kinetochore (GO:0034501), cell division (GO:0051301)

GO Molecular Function (3): enzyme binding (GO:0019899), kinetochore binding (GO:0043515), protein binding (GO:0005515)

GO Cellular Component (10): spindle pole (GO:0000922), outer kinetochore (GO:0000940), nucleus (GO:0005634), centrosome (GO:0005813), cytosol (GO:0005829), chromosome, centromeric region (GO:0000775), kinetochore (GO:0000776), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Mitotic Prometaphase	2
M Phase	2
Cell Cycle	2
Amplification of signal from the kinetochores	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
Mitotic Spindle Checkpoint	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle Checkpoints	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitotic cell cycle	3
cellular anatomical structure	3
intracellular membraneless organelle	3
binding	2
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
mitotic sister chromatid segregation	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
cell motility	1
protein localization to chromosome, centromeric region	1
protein localization to condensed chromosome	1
cellular process	1
protein binding	1
spindle	1
kinetochore	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
centriole	1
microtubule organizing center	1
cytoplasm	1
chromosomal region	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1424 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPDL1	HOXD13	P35453	868
SPDL1	ZW10	O43264	835
SPDL1	CD274	Q9NZQ7	814
SPDL1	PDCD1	Q15116	745
SPDL1	ZWILCH	Q9H900	683
SPDL1	PDCD1LG2	Q9BQ51	570
SPDL1	BICD2	Q8TD16	538
SPDL1	MTUS2	Q5JR59	475
SPDL1	CD8A	P01732	474
SPDL1	MTUS1	Q9ULD2	473
SPDL1	CEP126	Q9P2H0	470
SPDL1	RAB11FIP3	O75154	467
SPDL1	CTLA4	P16410	447
SPDL1	ERVFRD-1	P60508	447
SPDL1	ERV3-1	Q14264	446

IntAct

106 interactions, top by confidence:

A	B	Type	Score
CA8	SPDL1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SPDL1	USP15	psi-mi:“MI:0915”(physical association)	0.670
USP15	SPDL1	psi-mi:“MI:0915”(physical association)	0.670
NFKBIA	POLRMT	psi-mi:“MI:0914”(association)	0.670
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
SPDL1	RTP5	psi-mi:“MI:0915”(physical association)	0.560
PPP1R18	SPDL1	psi-mi:“MI:0915”(physical association)	0.560
SPDL1	DNAAF4	psi-mi:“MI:0915”(physical association)	0.560
SPDL1	TRAF4	psi-mi:“MI:0915”(physical association)	0.560
SPDL1	PPP1R18	psi-mi:“MI:0915”(physical association)	0.560
DNAAF4	SPDL1	psi-mi:“MI:0915”(physical association)	0.560
TRAF4	SPDL1	psi-mi:“MI:0915”(physical association)	0.560
	SPDL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (355): SPDL1 (Two-hybrid), SPDL1 (Two-hybrid), SPDL1 (Two-hybrid), SPDL1 (Two-hybrid), DYX1C1 (Two-hybrid), PPP1R18 (Two-hybrid), RTP5 (Two-hybrid), SPDL1 (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), HARS (Co-fractionation), PSMD14 (Co-fractionation), RPS5 (Co-fractionation)

ESM2 similar proteins: A0MZ66, A0MZ67, A6PWD2, A7MD70, B3DLE8, B9EKI3, F7DP49, O35550, O35551, O45420, P82094, Q05D60, Q08DR9, Q15276, Q28IH8, Q3KR99, Q3UIJ9, Q4L180, Q4R7H3, Q4V7C8, Q53EZ4, Q5BIX7, Q5R923, Q5RA03, Q5RI56, Q5U3Z6, Q6NRC9, Q6NRW2, Q6P0R8, Q6P402, Q6P6L0, Q7YS99, Q7Z7B0, Q861Q8, Q8BT07, Q8BVC4, Q8K2Q9, Q8K3K8, Q8K4T4, Q8R5M4

Diamond homologs: A7MD70, B3DLE8, Q08DR9, Q3KR99, Q4R7H3, Q5BIX7, Q6NRW2, Q923A2, Q96EA4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
USP45	“up-regulates activity”	SPDL1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mRNA transport	5	15.1×	8e-03
regulation of alternative mRNA splicing, via spliceosome	5	14.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

108 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	85
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
183325	NM_017785.5(SPDL1):c.1724_1747del (p.Ser575_Thr582del)	Likely pathogenic

SpliceAI

2098 predictions. Top by Δscore:

Variant	Effect	Δscore
5:169588391:CAGT:C	acceptor_loss	1.0000
5:169588392:A:AG	acceptor_gain	1.0000
5:169588392:AGTT:A	acceptor_gain	1.0000
5:169588392:AGTTG:A	acceptor_gain	1.0000
5:169588393:G:A	acceptor_loss	1.0000
5:169588393:G:GA	acceptor_gain	1.0000
5:169588393:GT:G	acceptor_gain	1.0000
5:169588393:GTT:G	acceptor_gain	1.0000
5:169588393:GTTG:G	acceptor_gain	1.0000
5:169588393:GTTGG:G	acceptor_gain	1.0000
5:169588491:G:GG	donor_gain	1.0000
5:169591043:TTCA:T	acceptor_loss	1.0000
5:169591044:TCA:T	acceptor_loss	1.0000
5:169591046:A:AG	acceptor_gain	1.0000
5:169591047:G:GG	acceptor_gain	1.0000
5:169591047:GA:G	acceptor_gain	1.0000
5:169591047:GAGT:G	acceptor_gain	1.0000
5:169591047:GAGTT:G	acceptor_gain	1.0000
5:169591171:G:GT	donor_gain	1.0000
5:169591200:GGAA:G	donor_gain	1.0000
5:169591201:G:GT	donor_gain	1.0000
5:169591201:G:T	donor_gain	1.0000
5:169593345:T:A	acceptor_gain	1.0000
5:169593346:G:A	acceptor_gain	1.0000
5:169593352:A:AG	acceptor_gain	1.0000
5:169593353:G:GT	acceptor_gain	1.0000
5:169593353:GA:G	acceptor_gain	1.0000
5:169593353:GAT:G	acceptor_gain	1.0000
5:169593353:GATA:G	acceptor_gain	1.0000
5:169593538:A:T	donor_gain	1.0000

AlphaMissense

4010 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:169594484:T:C	F258L	0.997
5:169594486:T:A	F258L	0.997
5:169594486:T:G	F258L	0.997
5:169594585:G:C	R265S	0.996
5:169594585:G:T	R265S	0.996
5:169594485:T:G	F258C	0.994
5:169596667:T:C	L333P	0.993
5:169599058:G:C	R408P	0.993
5:169594635:T:C	L282P	0.992
5:169599013:G:C	R393P	0.991
5:169591091:T:C	L68P	0.990
5:169594584:G:C	R265T	0.990
5:169599115:T:C	L427P	0.990
5:169594485:T:C	F258S	0.989
5:169594581:G:C	R264P	0.989
5:169594419:T:C	L236P	0.988
5:169594482:T:C	L257S	0.988
5:169599064:T:C	L410P	0.988
5:169588483:G:C	A23P	0.987
5:169593384:G:C	A123P	0.987
5:169588505:T:C	L30P	0.986
5:169594484:T:A	F258I	0.986
5:169596580:T:C	L304P	0.986
5:169594584:G:T	R265M	0.984
5:169588486:G:C	A24P	0.983
5:169594472:G:C	G254R	0.983
5:169594484:T:G	F258V	0.983
5:169594605:T:C	L272P	0.983
5:169599021:G:C	A396P	0.983
5:169599040:G:C	R402P	0.983

dbSNP variants (sampled 300 via entrez): RS1000038946 (5:169594457 G>A,C), RS1000045366 (5:169592442 C>G,T), RS1000374017 (5:169583834 G>A,C,T), RS1000524655 (5:169589546 C>A,T), RS1000619363 (5:169587962 C>G), RS1000636582 (5:169596133 A>G), RS1000649608 (5:169593851 T>A), RS1000709532 (5:169595500 A>G), RS1000743569 (5:169583669 C>T), RS1000795066 (5:169601850 C>A,T), RS1001095855 (5:169600135 T>G), RS1001133896 (5:169595759 C>G), RS1001155557 (5:169601216 C>G), RS1001301556 (5:169600956 G>A,T), RS1001727947 (5:169584394 C>G,T)

Disease associations

OMIM: gene MIM:616401 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly	Limited	Autosomal recessive

Mondo (1): microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000838_2	Waist circumference	5.000000e-06
GCST012307_7	Bipolar disorder x sex interaction	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008343	sex interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, increases reaction, decreases response to substance, decreases expression (+1 more)	4
bisphenol A	decreases expression	3
Air Pollutants	increases abundance, increases expression, decreases expression	3
Cyclosporine	decreases expression	3
Arsenic	affects cotreatment, decreases expression, increases abundance, decreases abundance, increases export	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	decreases expression	1
methylparaben	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
jinfukang	decreases expression, affects cotreatment	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

17 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.